Defining and Targeting Novel Epigenetic Vulnerabilities in Heterogeneous Drug-Resistant Melanomas
Abstract
In this study, we perform a targeted kinase inhibitor screen and identify a tool compound, named MTX-216, to be highly effective in blocking NF1-LoF melanoma cells. Single-cell analysis links drug-induced cytotoxicity to effective co-suppression of proliferation markerKi-67 and the ribosomal S6 phosphorylation. We find the anti-tumor efficacy of MTX-216 to be dependent on its ability to inhibit not only PI3K but also SYK and suppression of a group of genes that regulate mitochondrial electron transport chain. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown show favorable effects. These studies provide a path to exploit SYK dependency to selectively block NF1-LoF melanoma cells. In parallel, through systematic experimental measurements, single-cell analysis, and long-duration live-cell microscopy experiments, we have identified potentially novel effective drugs or drug combinations that overcome cell-to cell variability responsible for incomplete efficacy of currently available MAPK inhibitor treatments across genetically diverse BRAF-mutant melanoma contexts.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2023
- Accession Number
- AD1205944
Entities
People
- Mohammad Fallahi-Sichani
Organizations
- University of Virginia